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Trypanocidal Drug Benznidazole Impairs Lipopolysaccharide Induction of Macrophage Nitric Oxide Synthase Gene Transcription Through Inhibition of NF-B Activation¹

Eliane Piaggio^*,, Josiane Sancéau, Silvia Revelli^*, Oscar Bottasso^2,*, Juana Wietzerbin and Esteban Serra

^* Facultad de Ciencias Médicas, Instituto de Immunología, Rosario, Argentina; Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Biología Molecular y Celular de Rosario Consejo Nacional de Invetigaciones Cientìficas y Técnicas de Argentina, Rosario, Argentina; and Institut National de la Santé et de la Recherche Médicale Unite 365, Institut Curie, Section de Recherche, Paris, France

In murine macrophages, inducible NO synthase II (NOSII) gene expression is promoted at a transcriptional level by LPS and/or IFN- with benznidazole (BZL), a trypanocidal drug, acting to down-regulate NOSII gene induction and hence inhibiting NO production. By performing transient transfection experiments, we now report that BZL also inhibited the expression of NOSII gene promoter or multimerized NF-B binding site controlled reporter genes. By contrast, no effect was observed on the expression of a reporter gene under the control of the NOSII promoter-derived IFN regulatory factor element. EMSAs demonstrated that BZL inhibited the nuclear availability of NF-B in stimulated macrophages. NF-B is activated in macrophages by phosphorylation, ubiquitination, and subsequent proteolysis of IB. Within this setting, Western blot was also performed to show that BZL blocked IB degradation. Collectively, these results demonstrate that BZL is able to specifically inhibit macrophage NF-B activation after LPS plus IFN- stimulation.